Antifungal agents

ABSTRACT

The invention provides a pyrrole compound, which compound is (a) 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a deuterated derivative thereof, or (b) 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide or a deuterated derivative thereof, or (c) a prodrug of compound (a) or a prodrug of compound (b), or a pharmaceutically acceptable salt or agriculturally acceptable salt of (a), (b) or (c). Also provided are combinations and compositions comprising the compound and known antifungal agents. The invention also relates to the therapeutic use of a compound of the invention in prevention or treatment of fungal diseases. It also relates to the use of: 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide or an agriculturally acceptable salt thereof, or 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide or an agriculturally acceptable salt thereof, as an agricultural fungicide.

FIELD OF THE INVENTION

This invention relates to pyrrole compounds, combinations andcompositions comprising a pyrrole compound and a further antifungalagent, and their therapeutic use in prevention or treatment of fungaldiseases. It also relates to the use of the compound, combinations andcompositions as agricultural fungicides.

BACKGROUND OF THE INVENTION

Invasive fungal infections are well recognised as diseases of theimmunocompromised host. Over the last twenty years there have beensignificant rises in the number of recorded instances of fungalinfection. In part this is due to increased awareness and improveddiagnosis of fungal infection. However, the primary cause of thisincreased incidence is the vast rise in the number of susceptibleindividuals. This is due to a number of factors including new andaggressive immunosuppressive therapies, increased survival in intensivecare, increased numbers of transplant procedures and the greater use ofantibiotics worldwide.

In certain patient groups, fungal infection occurs at high frequency;lung transplant recipients have a frequency of up to 20% colonisationand infection with a fungal organism and fungal infection in allogenichaemopoetic stem cell transplant recipients is as high as 15% (Ribaud etal., 1999, Clin Infect Dis. 28:322-30).

Recently there has been increased awareness of the contribution offungal sensitisation, colonisation, allergy and localised infection inthe exacerbation of existing respiratory diseases. Here fungi have beenimplicated in asthma, COPD, brochiectasis and cystic fibrosis. Allergicbronchopulmonary aspergillosis (ABPA) is a lower respiratory tractcondition caused by fungal colonisation, typically by Apsergillusfumigatus. ABPA can be seen is asthmatics at a rate of 0.7-3.5% andcystic fibrosis at a rate of 7-9%.

Currently there are four classes of antifungal drug are available totreat systemic fungal infections. These are the polyenes (e.g.,amphotericin B), the azoles (e.g., ketoconazole or itraconazole), theechinocandins (e.g., caspofungin) and flucytosine.

The polyenes are the oldest class of antifungal agent being firstintroduced in the 1950's. The exact mode of action remains unclear butpolyenes are only effective against organisms that contain sterols intheir outer membranes. It has been proposed that amphotericin Binteracts with membrane sterols to produce pores allowing leakage ofcytoplasmic components and subsequent cell death.

Azoles work by inhibition of the 14α-demethylase via a cytochromeP450-dependent mechanism. This leads to a depletion of the membranesterol ergosterol and the accumulation of sterol precursors resulting ina plasma membrane with altered fluidity and structure.

Echinocandins work by the inhibition of the cell wall synthetic enzymeβ-glucan synthase. This leads to abnormal cell wall formation, osmoticsensitivity and cell lysis.

Flucytosine is a pyrimidine analogue interfering with cellularpyrimidine metabolism as well DNA, RNA and protein synthesis. Howeverwidespread resistance to flucyotosine limits its therapeutic use.

It can be seen that to date the currently available antifungal agentsact primarily against only two cellular targets; membrane sterols(polyenes and azoles) and β-glucan synthase (echinocandins).

Resistance to both azoles and polyenes has been widely reported leavingonly the recently introduced echinocandins to combat invasive fungalinfections. As the use of echinocandins increases, resistance by fungiwill inevitably occur.

The identification of new classes of antifungal agent is required togive the promise of positive therapeutic outcomes to patients.

Pyrrole compounds have also been identified as antifungal agents. WO2009 130481 discloses pyrrole compounds that may be used in theprevention or treatment of fungal disease.

SUMMARY OF THE INVENTION

The present inventors have found that the pyrrole compound2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideis a particularly effective antifungal agent. It shows high potency inenzyme inhibition and fungal inhibition tests and has goodbioavailability and low toxicity. Tests have shown that this pyrrolecompound inhibits the growth of a wide variety of fungi, in particularthe human pathogenic fungi Aspergillus. This particular compound hasbeen shown to have activity against a wider spectrum of species withinthe Aspergillus genus than other, previously known, pyrrole compounds.Further, the compound has been shown to exhibit increased in vivoefficacy when compared to the known antifungal drug Voriconazole, inparticular improved efficacy against Scedosporium fungi. The compound-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamidemay, therefore, be used to effectively treat a wide variety of fungalinfection and disease.

It has also been found that2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamidealso exhibits good activity. The addition of a hydroxyl on the phenyladjacent to the piperazinyl group aids solubility and permeability.

Deuterated derivates of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideand2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamidehave also been found to be highly active.

Accordingly, the present invention provides a compound, which compoundis:

-   (a)    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide    or a deuterated derivative thereof, or-   (b)    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide    or a deuterated derivative thereof, or-   (c) a prodrug of (a) or (b), or    a pharmaceutically acceptable salt or agriculturally acceptable salt    of (a), (b) or (c).

In one instance the compound is a pharmaceutical compound, whichpharmaceutical compound is:

-   (a)    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide    or a deuterated derivative thereof, or-   (b)    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide    or a deuterated derivative thereof, or-   (c) a prodrug of (a) or (b), or    a pharmaceutically acceptable salt of (a), (b) or (c).

In another instance, the compound is an agricultural compound, whichagricultural compound is:

-   (a)    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,    or-   (b)    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide,    or    an agriculturally acceptable salt of (a) or (b).

In another instance, the compound is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt or agriculturally acceptable saltthereof.

The present invention also provides a pharmaceutical compositioncomprising a pharmaceutical compound of the invention together with oneor more pharmaceutically acceptable carriers and/or excipients.

Also provided is an agricultural composition comprising: (a)2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof; or (b)2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof. Typically, theagricultural composition also comprises one or more agriculturallyacceptable carriers and/or diluents.

In another aspect, the invention provides a pharmaceutical combinationcomprising: (i) a pharmaceutical compound of the invention; and (ii) asecond antifungal agent.

In yet another aspect, the invention provides a pharmaceutical compoundof the invention, a composition as defined above or a combination asdefined above for use in a method of treatment of the human or animalbody by therapy.

The invention also provides a pharmaceutical compound of the invention,a composition as defined above or a combination as defined above for usein the prevention or treatment of fungal disease.

In another aspect, the invention provides a kit comprising, in admixtureor in separate containers, a pharmaceutical compound of the inventionand a second antifungal agent. The kit typically comprises instructionsfor administration of the pharmaceutical compound and the secondantifungal agent.

Also provided by the invention is a method of controlling a fungaldisease in a plant, which method comprises applying to the locus of theplant a compound which is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof; and optionally a secondantifungal agent.

The invention also provides the use of a compound, which compound is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof; optionally together with asecond antifungal agent, as an agricultural fungicide.

In another aspect, the invention provides a method of preventing ortreating fungal disease in a subject which method comprisesadministering to said subject an effective amount of a pharmaceuticalcompound of the invention, a composition as defined above or acombination as defined above.

In yet another aspect, the invention provides the use of apharmaceutical compound of the invention, a composition as defined aboveor a combination as defined above in the manufacture of a medicament forthe prevention or treatment of fungal disease.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides NMR data for 2-(1,5-Dimethyl-3-phenyl-1H-pyrro-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamideNMR (400 MHz, CDCl₃)).

FIG. 2a provides NMR data for2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideNMR (400 MHz, CDCl₃)).

FIG. 2b provides NMR data for 5-(2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamido)-2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl2-(1,4-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetate NMR (400 MHz,CDCl₃)).

FIG. 3 provides NMR data for2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)phenyl)-2-oxoacetamideNMR (400 MHz, CDCl₃)).

FIG. 4 provides NMR data for2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl-2,3,5,6-d₄)-2-oxoacetamideNMR (400 MHz, CDCl₃)).

FIG. 5 provides the survival curves obtained in a survival study,discussed below, which looked at the survival of mice receiving variousoral dosages of 2-(1,5-Dimethyl-3-phenyl-1H-pyrro-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide.

FIG. 6 provides the mean serum galactomannan indices obtained in thesurvival study.

FIG. 7 shows the cumulative mortality of immunosuppressed mice infectedwith L. prolificans FMR 3569 when treated with (a) VRC, voriconazole at25 mg/kg p.o, by gavage QD; (b) Example 1 at 20 mg/k, p.o, by gavage BIDand (c) no treatment.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a compound, which compound is

(a)

2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a deuterated derivative thereof, or(b)

2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor a deuterated derivative thereof, or(c) a prodrug of compound (a) or a prodrug of compound (b), ora pharmaceutically acceptable salt or agriculturally acceptable salt of(a), (b) or (c).

The compound may, for instance, be2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt or agriculturally acceptable saltthereof, in particular2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof.

Alternatively, the compound may be2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor a pharmaceutically acceptable salt or agriculturally acceptable saltthereof, in particular2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor a pharmaceutically acceptable salt thereof. As mentioned above, theaddition of the hydroxyl group aids solubility and permeability. Inparticular, the inclusion of the hydroxyl group lowers c Log P andincreases the PSA (polar surface area). The c Log P value of a compoundis the logarithm of its partition coefficient between n-octanol andwater log(coctanol/cwater). It provides a measure of the hydrophilicityof a compound. A suitable method for measuring Log P can be found in“Leo et al., Chem. Rev., 1971, 71 (6), pp 525-616”. A suitable methodfor measuring PSA can be found in “Ertl, P. ei al., J. Med. Chem. 2000,43: 3714-3717”.

For the avoidance of doubt, the compound can, if desired, be used in theform of solvates. Further, for the avoidance of doubt, the compound maybe used in any tautomeric form.

As used herein, a pharmaceutically acceptable salt is a salt with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids such as hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic, hydroiodic or nitric acid andorganic acids such as citric, fumaric, maleic, malic, ascorbic,succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic,benzenesulphonic, p-toluenesulphonic acid, formic, acetic, propionic,glycolic, lactic, pyruvic, oxalic, salicylic, trichloroacetic, picric,trifluoroacetic, cinnamic, pamoic, malonic, mandelic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, EDTA, p-aminobenzoic or glutamic acid, sulfates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates or ketoglutarates. Furtherexamples of pharmaceutically acceptable inorganic or organic acidaddition salts include the pharmaceutically acceptable salts listed inJournal of Pharmaceutical Science, 66, 2 (1977) which are known to theskilled artisan. Pharmaceutically acceptable bases include alkali metal(e.g. sodium or potassium) and alkali earth metal (e.g. calcium ormagnesium) hydroxides and organic bases such as alkyl amines, aralkylamines and heterocyclic amines, lysine, guanidine, diethanolamine andcholine.

Also intended as pharmaceutically acceptable acid addition salts are thehydrates which the present compound is able to form.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

The compound may form solvates with standard low molecular weightsolvents using methods known to the skilled artisan.

Prodrug

The present invention also provides a prodrug of compound (a) or aprodrug of compound (b). The compound may, for example, be a prodrug of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor the compound may be a prodrug of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide.The prodrug may, for instance, provide enhanced solubility,permeability, adsorption, distribution and formulation, and/or lowertoxicity.

A prodrug is an analogue of the compound of the invention which will beconverted in vivo to the desired active compound. Suitable methods willbe known to those skilled in the art.

Particularly suitable prodrugs include those in which a nitrogen atom ofthe compound is quaternised by addition of an ester or alkyl estergroup. For example, the nitrogen atom of an amine group may bequaternised by addition of a —CH₂—O—COR group, wherein R is typicallymethyl or tert-butyl.

Other suitable prodrugs include those in which a moiety is added to thephenyl ring adjacent to the piperazinyl group. Relative to the amide(—NH—CO—) moiety, the moiety may be added to the phenyl ring at theortho or meta position, preferably at the meta position. The prodrugmay, for instance, have the general formula:

wherein R is a group of formula —O—CO—OR¹, —O—CO—R¹, —O—CO—NR¹R²,—O—CO—(CH₂)_(z)—NR¹R², —OR¹, —O—(CR¹R²)_(z)—O—CO—R³⁻, —O—P(O)(OR⁴)(OR⁵)or —O—(CH₂)_(z)—O—P(O)(OR⁴)(OR⁵), wherein: R¹, R² and R³ areindependently hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6cycloalkyl, an unsubstituted 5- to 7-membered heterocyclyl group, or a5- to 7-membered heterocyclyl group substituted with up to threesubstituents selected from C1-C4 alkyl and C1-C4 alkoxy; R⁴ and R⁵ areindependently hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or agroup I element such as Na; and z is 1, 2, 3 or 4.

As used herein, a C1-C4 alkyl group or moiety can be linear or branchedbut is preferably linear. Suitable such alkyl groups and moietiesinclude methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl andtert-butyl.

As used herein, a C2-C4 alkenyl group or moiety can be linear orbranched but is preferably linear. It contains one or more carbon-carbondouble bonds. It is preferably a C2-C3 alkenyl group. Suitable suchalkenyl groups and moieties include vinyl, allyl, propenyl and butenyl,e.g. CH₂C(Me)=CH₂.

As used herein, a C2-C4 alkynyl group or moiety can be linear orbranched but is preferably linear. It contains one or more carbon-carbontriple bonds. It is preferably a C2-C3 alkynyl group. Suitable alkynylgroups and moieties include ethynyl, propynyl, and butynyl, and isomersthereof.

As used herein, a C3-C6 cycloalkyl group is typically a C4, C5 or C6cycloalkyl group, more preferably a C5 or C6 cycloalkyl group.

An alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted.

As used herein and unless otherwise stated, a heterocyclyl group ormoiety is a saturated 5- to 7-membered ring system in which the ringcontains at least one heteroatom. Typically, the ring contains up tothree heteroatoms, e.g. one or two heteroatoms, selected from O, S andN. Thus, a heterocyclyl group or moiety is typically a 5- to 7-memberedring containing one, two or three heteroatoms selected from O, S and N.Suitable such heterocyclyl groups and moieties include, for example,monocyclic saturated 5- to 7-membered rings, more preferably monocyclicsaturated 5- to 6-membered rings such as tetrahydrofuranyl, piperidinyl,oxazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, dioxolanyl,piperidonyl, piperazinyl, tetrahydropyranyl and 1,4-diazepanyl, morepreferably pyrrolidinyl, piperazinyl, tetrahydropyranyl and piperidinyl.

A heterocyclyl group may be substituted or unsubstituted. Each ring atommay be unsubstituted or may carry one or two substituents. If desired, anitrogen atom may be disubstituted and a sulphur atom may besubstituted, providing a charged heteroatom. Typically, a heterocyclylgroup carries up to three substituents, e.g. one or two substituents.The heterocycle may be connected to the remainder of the molecule by abond to any of its available ring positions. Suitable substituents areC1-C4 alkyl and C1-C4 alkoxy, e.g. methyl, ethyl, methoxy and ethoxy,preferably methyl.

Preferably, R¹, R² and R³ are independently hydrogen, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, or an unsubstituted 5- to6-membered heterocyclyl group. More preferably, R¹, R² and R³ areindependently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or anunsubstituted pyrrolidinyl, piperazinyl, tetrahydropyranyl orpiperidinyl group.

Preferably, R⁴ and R⁵ are independently hydrogen, C1-C4 alkyl, or agroup I element such as Na. More preferably, R⁴ and R⁵ are independentlyhydrogen, methyl, ethyl, or Na.

Preferably, z is 1 or 2. More preferably z is 1.

Preferably R is a group of formula —O—CO—OR¹, —O—CO—R¹, —O—CO—NR¹R²,—O—CO—(CH₂)_(z)—NR¹R², —OR¹, —O—(CR¹R²)_(z)—O—CO—R³ or—O—P(O)(OR⁴)(OR⁵). More preferably, R is a group of formula —O—COR¹,—O—CO—NR¹R², —O—CO—(CH₂)_(z)—NR¹R², —OR¹, —O—(CR¹R²)_(z)—O—CO—R³ or—O—P(O)(OR⁴)(OR⁵).

In one embodiment, R is a group of formula —O—CO—OR¹, —O—CO—R¹,—O—CO—NR¹R², —O—CO—(CH₂)_(z)—NR¹R², —OR, —O—(CR¹R²)_(z)—O—CO—R³ or—O—P(O)(OR⁴)(OR⁵), wherein: R¹, R² and R³ are independently hydrogen,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, or anunsubstituted 5- to 6-membered heterocyclyl group; R⁴ and R⁵ areindependently hydrogen, C1-C4 alkyl, or a group I element such as Na;and z is 1 or 2. More preferably R is a group of formula —O—COR¹,—O—CO—NR¹R², —O—CO—(CH₂)_(z)—NR¹R², —OR¹, —O—(CR¹R²)_(z)—O—CO—R³ or—O—P(O)(OR⁴)(OR⁵), wherein R¹, R² and R³ are independently hydrogen,C1-C4 alkyl, C3-C6 cycloalkyl, or an unsubstituted pyrrolidinyl,piperazinyl, tetrahydropyranyl or piperidinyl group; R⁴ and R⁵ areindependently hydrogen, methyl, ethyl, or Na; and z is 1.

R may, for example, be —OP(O)(ONa)₂, —OP(O)(OH)₂, —OC(═O)CH₂N(H)CH₃,—OC(═O)C₄NH₈, —OC(═O)CH₃, —OC(═O)N(CH₃)₂ or —OCH₂OC(═O)C(CH₃)₃.

In one embodiment, the compound is a pharmaceutically acceptable salt ofthe prodrug.

Deuterated Derivative

The compound of the invention may be a deuterated derivative of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide.Deuterated derivatives of the compounds of the invention have been foundto be highly active antifungal agents.

The term deuterated derivative as used herein refers to a compound inwhich at least one hydrogen atom has been replaced with deuterium, forinstance, from 1 to 10 hydrogen atoms may be replaced with deuterium.Two or more hydrogen atoms may be replaced with deuterium. For example,all of the hydrogen atoms on a particular ring within the compound ofthe invention may be replaced with deuterium.

When, for example, the compound is a deuterated derivative of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide:

(a) all of the hydrogen atoms on the piperazinyl ring may be replacedwith deuterium

(b) all of the hydrogen atoms on the phenyl ring adjacent to thepiperazinyl ring may be replaced with deuterium

or(c) all of the hydrogen atoms on the pyrimidinyl ring may be replacedwith deuterium

Preferably, (a) all of the hydrogen atoms on the piperazinyl ring arereplaced with deuterium, or (b) all of the hydrogen atoms on the phenylring adjacent to the piperazinyl ring are replaced with deuterium.

When, for example, the compound is a deuterated derivative of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide:

(a) all of the hydrogen atoms on the piperazinyl ring may be replacedwith deuterium

or(b) all of the hydrogen atoms on the phenyl ring adjacent to thepiperazinyl ring may be replaced with deuterium

or(c) all of the hydrogen atoms on the pyrimidinyl ring may be replacedwith deuterium

Preferably, (a) all of the hydrogen atoms on the piperazinyl ring arereplaced with deuterium, or (b) all of the hydrogen atoms on the phenylring adjacent to the piperazinyl ring are replaced with deuterium.

The compound may, for example, be a pharmaceutically acceptable salt ofthe deuterated derivative.

Synthesis

In one embodiment, the compound of the invention is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof.

The compound may be synthesised by reacting a compound of formula (II),with a compound of formula (III). Typically the reaction takes place inthe presence of an organic solvent and a base. Preferably the solvent isdichloromethane or tetrahydrofuran and the base is triethylamine orpyridine. Typically the reaction is carried out at 0° C. initially whilethe reagents are added and then stirred at room temperature until thereaction is complete. The compound of formula (III) is typicallyavailable from commercial sources or can be prepared by known methods.

The compound of formula (II) may be prepared by reacting a compound offormula (IV), with preferably oxalyl chloride. Typically the reactiontakes place in an organic solvent. Preferably, the solvent isdichloromethane. Typically, the reaction is carried out at 0° C.initially while the reagents are added and then stirred at roomtemperature until the reaction is complete.

All of the starting materials referred to in the reactions describedabove are available from commercial sources or can be prepared byanalogy with known methods.

In another embodiment, the compound of the invention is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof. In this embodiment,compound (III) has an OH group on the phenyl ring, meta to the —NH₂group.

Deuterated derivates may be synthesised from deuterated startingmaterials, wherein hydrogen atoms in the starting materials are replacedwith deuterium as appropriate to arrive at the target product. Forexample, to synthesise a deuterated derivative in which the hydrogenatoms on the piperazinyl ring are replaced with deuterium, compound(III) above may comprise deuterium in place of hydrogen on thepiperazinyl ring.

The experimental section provides specific synthetic examples.

Pharmaceutical Composition

In one embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutical compound of the invention,together with one or more pharmaceutically acceptable carriers and/orexcipients.

The composition may, for instance, comprise a compound, which compoundis2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a pharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable carriers and/or excipients.

The pharmaceutical composition of the invention typically contains up to85 wt % of the pharmaceutical compound (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a pharmaceutically acceptable salt thereof). More typically, itcontains up to 50 wt % of the pharmaceutical compound (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a pharmaceutically acceptable salt thereof). Preferred pharmaceuticalcompositions are sterile and pyrogen free.

Pharmaceutical Combination

The present invention also provides a pharmaceutical combinationcomprising: (i) a pharmaceutical compound of the invention, and (ii) asecond antifungal agent.

The combination may, for example, comprise: (i) a compound which is2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof; and (ii) a secondantifungal agent.

Typically, the pharmaceutical combination is a pharmaceuticalcombination in which pharmaceutical compound (i) and second antifungalagent (ii) are formulated for separate, simultaneous or successiveadministration. For simultaneous administration, (i) and (ii) may forexample be provided in a single composition. For separate or successiveadministration, (i) and (ii) may, for example, be provided as a kit.

The second antifungal agent used in the invention can be any suitableantifungal agent that the skilled person would judge to be useful in thecircumstances. Particularly suitable classes of antifungal agentsinclude azoles, polyenes, purine nucleotide inhibitors, pyrimidinenucleotide inhibitors, mannan inhibitors, protein elongation factorinhibitors, chitin synthase inhibitors, Beta-glucan synthase inhibitors,echinocandins, allylamines, anti-HSP90 antibodies,bactericidal/permeability inducing protein products and polyoxins. Othersuitable antifungal agents which do not fall within the classes aboveinclude the compounds 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborale(AN269), 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborale (AN2718) andicofungipen. For instance, the second antifungal agent may be selectedfrom the group consisting of azoles, polyenes, purine nucleotideinhibitors, pyrimidine nucleotide inhibitors, mannan inhibitors, proteinelongation factor inhibitors, echinocandins, allylamines, anti-HSP90antibodies, bactericidal/permeability inducing protein products orpolyoxins, or one of the compounds5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborale (AN269),5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborale (AN2718), icofungipen,VT116 or SCY078.

VT116 is 2-Pyridineethanol,α-(2,4-difluorophenyl)-β,β-difluoro-α-(1H-tetrazol-1-ylmethyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-,(αR)-,

and SCY078 078 (aka MK-3118) is a semi-synthetic derivative ofenfumafungin, 4H-1,4a-Propano-2H-phenanthro[1,2-c]pyran-7-carboxylicacid,15-[(2R)-2-amino-2,3,3-trimethylbutoxy]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-,(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R):

Preferred azoles are clotrimazole, econazole, bifonazole, butoconazole,fenticonazole, fluconazole, isoconazole, itraconazole, ketoconazole,miconazole, oxiconazole, sertaconazole, sulconazole, tioconazole,isavuconazole, ravuconazole, posaconazole, terconazole and voriconazole,luliconazole. Preferred echinocandins are anidulafungin, caspofunginmicafungin and biafungin. Preferred allylamines are terbinafine,butenafine, amorolfine and naftifine. Preferred polyenes areamphotericin B and nystatin. A preferred example of a purine orpyrimidine nucleotide inhibitor is flucytosine. A preferred mannaninhibitor is pradamicin. A preferred protein elongation factor inhibitoris sordarin and analogues thereof. A preferred polyoxin is nikkomycin Z.

Particularly preferred second antifungal agents are caspofungin,micafungin, anidulofungin, amphotericin B, voriconazole, posaconazole,isavuconazole, fluconazole and itraconazole.

The pharmaceutical combination may be formulated as a singlecomposition. Thus, the pharmaceutical composition may, for example,comprise (i) a pharmaceutical compound of the invention (e.g.2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), (ii) a second antifungalagent as defined herein, and (iii) a pharmaceutically acceptable carrieror diluent.

Medical Uses

In one embodiment, (i) a pharmaceutical compound of the invention, e.g.2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof, (ii) a pharmaceuticalcomposition as defined herein or (iii) a pharmaceutical combination asdefined herein, may be for use in a method of treatment of the human oranimal body by therapy.

Accordingly, (i) a pharmaceutical compound of the invention, (ii) apharmaceutical composition as defined herein or (iii) a pharmaceuticalcombination as defined herein, may be for use in the prevention ortreatment of fungal disease, for example, (i) or (ii) may be used incombination with a second antifungal agent. In particular,2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof may be used in combinationwith a second antifungal agent, as desired. The second antifungal agentmay be a second antifungal agent as defined herein.

The pharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), pharmaceuticalcombinations of the invention and pharmaceutical compositions of theinvention may be administered in a variety of dosage forms. Thus, it canbe administered orally, for example as a tablet, troche, capsules,lozenge, aqueous or oily suspension, dispersible powder or granules. Thepharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), pharmaceuticalcombinations of the invention and pharmaceutical compositions of theinvention may also be administered parenterally, either subcutaneously,intravenously, intramuscularly, intrasternally, transdermally or byinfusion techniques, for example, pharmaceutical combinations of theinvention and pharmaceutical compositions of the invention may beadministered intravenously. Depending on the vehicle and concentrationused, the drugs can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as a local anaesthetic, preservative andbuffering agent can be dissolved in the vehicle. The pharmaceuticalcompound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof,) pharmaceuticalcombinations, and pharmaceutical compositions may also be administeredas suppositories. The pharmaceutical compound of the invention (forexample2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), pharmaceuticalcombinations and pharmaceutical compositions may be administered byinhalation in the form of an aerosol via an inhaler or nebuliser. Thepharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), pharmaceuticalcombinations and pharmaceutical compositions may be administeredtopically, for example, as a cream, foam, gel, lotion, or ointment.

The pharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), and optionally a secondantifungal agent, is typically formulated for administration with apharmaceutically acceptable carrier or diluent. For example, solid oralforms may contain, together with the active compound, solubilisingagents, e.g. cyclodextrins or modified cyclodextrins; diluents, e.g.lactose, dextrose, saccharose, cellulose, corn starch or potato starch;lubricants, e.g. silica, talc, stearic acid, magnesium or calciumstearate, and/or polyethylene glycols; binding agents; e.g. starches,arabic gums, gelatin, methylcellulose, carboxymethylcellulose orpolyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid,alginates or sodium starch glycolate; effervescing mixtures; dyestuffs;sweeteners; wetting agents, such as lecithin, polysorbates,laurylsulphates; and, in general, non-toxic and pharmacologicallyinactive substances used in pharmaceutical formulations. Suchpharmaceutical preparations may be manufactured in known manner, forexample, by means of mixing, granulating, tabletting, sugar-coating, orfilm coating processes.

Liquid dispersions for oral administration may be solutions, syrups,emulsions and suspensions. The solutions may contain solubilising agentse.g. cyclodextrins or modified cyclodextrins. The syrups may contain ascarriers, for example, saccharose or saccharose with glycerine and/ormannitol and/or sorbitol.

Suspensions and emulsions may include pharmaceutically active compoundsin which the average particle size has undergone particle size reductionby micronisation or nanonisation technologies. For instance, the averageparticle size of the compound of the invention may have undergoneparticle size reduction by micronisation or nanonisation technologies.

Suspensions and emulsions may contain as carrier, for example a naturalgum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspensions orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g. sterilewater, olive oil, ethyl oleate, glycols, e.g. propylene glycol;solubilising agents, e.g. cyclodextrins or modified cyclodextrins, andif desired, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous or infusions may contain as carrier, forexample, sterile water and solubilising agents, e.g. cyclodextrins ormodified cyclodextrins, or preferably they may be in the form ofsterile, aqueous, isotonic saline solutions.

Nanoformulations are also envisaged.

For topical application to the skin, the compound may, for example, bemade up into a cream, lotion or ointment. Cream or ointment formulationswhich may be used for the drug are conventional formulations well knownin the art, for example as described in standard textbooks ofpharmaceutics such as the British Pharmacopoeia.

For topical application by inhalation, the compound may be formulatedfor aerosol delivery for example, by pressure-driven jet atomizers orultrasonic atomizers, or preferably by propellant-driven meteredaerosols or propellant-free administration of micronized powders, forexample, inhalation capsules or other “dry powder” delivery systems.Excipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, and fillers (e.g. lactose in thecase of powder inhalers) may be present in such inhaled formulations.For the purposes of inhalation, a large number of apparata are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g. Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inparticular in the case of powder inhalers, a number of technicalsolutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or theinhalers for example as described in European Patent Application EP 0505 321).

For topical application to the eye, the compound may be made up into asolution or suspension in a suitable sterile aqueous or non aqueousvehicle. Additives, for instance buffers such as sodium metabisulphiteor disodium edeate; preservatives including bactericidal and fungicidalagents such as phenyl mercuric acetate or nitrate, benzalkonium chlorideor chlorhexidine, and thickening agents such as hypromellose may also beincluded.

A therapeutically effective amount of a pharmaceutical compound of theinvention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) may be administered to apatient. A typical daily dose is up to 200 mg, e.g. up to 100 mg or upto 50 mg per kg of body weight, for example from 0.001 to 200 or 0.001to 50 mg per kg of body weight, according to the activity of thepharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) or combination ofspecific antifungal agents used, the age, weight and conditions of thesubject to be treated, the type and severity of the disease and thefrequency and route of administration. Preferably, daily dosage levelsare up to 200 mg, e.g. up to 150 mg, up to 100 mg, up to 50 mg or up to40 mg per kg of body weight. Daily dosage levels are for example atleast 1 mg, at least 2 mg or at least 5 mg per kg of body weight. In oneembodiment the daily dosage level is from 0.05 mg to 2 g, preferablyfrom 0.1 mg to 10 mg. Where a combination is administered, apharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) is typically administeredin an amount of at least 0.05 mg, preferably at least 0.1 mg, 2 mg or atleast 5 mg. A preferred upper limit on the amount of compound of theinvention administered is typically 200 mg, e.g. 100 mg, 50 mg or 25 mg.The second antifungal agent is typically administered at or below thestandard dose used for that drug. An advantage of the combinations ofthe present invention is that known antifungal agents may beadministered in lower doses than are currently used, resulting in areduction in toxic effects. The pharmaceutical compound of the invention(for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), combination of theinvention or composition of the invention is typically administered tothe patient in a non-toxic amount.

When, for example, a pharmaceutical compound of the invention (forexample2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) is part of apharmaceutical combination as defined herein, formulated for separate,simultaneous or successive administration, (a) a pharmaceutical compoundof the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof), and (b) the secondantifungal agent may be administered by the same mode of administrationor by different modes of administration.

Typically, the pharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) is for use in theprevention or treatment by intravenous administration of a fungaldisease. Thus, typically, the pharmaceutical compound of the invention(for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) is administeredintravenously. If a second antifungal agent is administered separately,simultaneously or successively, the second antifungal agent may beadministered intravenously or by a different mode of administration,which different mode of administration may be as defined herein.

Preferably, the fungal disease comprises an infection by a fungus, forexample an Ascomycete. Preferably, the fungal disease comprises aninfection by an organism selected from the genera Absidia; Acremonium;Alternaria; Aspergillus; Bipolaris; Blastomyces; Blumeria; Cladosporium;Coccidioides; Colletotrichium; Curvularia; Encephalitozoon; Epicoccum;Epidermophyton; Exophiala; Exserohilum; Fusarium; Histoplasma;Leptosphaeria; Microsporum; Mycosphaerella; Neurospora, Paecilomyces;Penicillium, Phytophthora; Plasmopara; Pneumocystis; Pyricularia;Pythium; Puccinia; Rhizoctonia; Rhizomucor; Scedosporium;Scopulariopsis; Trichophyton; Trichosporon; and Ustilago.

Preferably, the fungal disease comprises an infection by an organism ofthe genus Aspergillus, Scedosporium or Fusarium, for instance, thefungal disease comprises an infection by an organism of the genusAspergillus or Scedosporium, in particular Aspergillus. In oneembodiment, the fungal disease comprises an infection by an organism ofthe genus Aspergillus. In another embodiment, the fungal diseasecomprises an infection by an organism of the genus Scedosporium.

Preferably, the fungal disease comprises an infection by an organismselected from the species Absidia corymbifera; Acremonium spp;Alternaria alternata; Aspergillus flavus; Aspergillus fumigatus;Aspergillus nidulans; Aspergillus niger; Aspergillus parasiticus;Aspergillus terreus; Bipolaris spp; Blastomyces dermatitidis; Blumeriagraminis; Cladosporium cladosporoides; Cladosporium herbarium;Coccidioides immitis; Coccidioides posadasii; Curvularia lunata;Colletotrichium trifolii; Encephalitozoon cuniculi; Epicoccum nigrum;Epidermophyton floccosum; Exophiala spp; Exserohilum rostratum; Fusariumgraminarium; Fusarium solani; Fusarium sporotrichoides; Histoplasmacapsulatum; Leptosphaeria nodorum; Microsporum canis; Mycosphaerellagraminicola; Paecilomyces lilanicus; Paecilomyces varioti; Penicilliumchrysogenum; Phytophthora capsici; Phytophthora infestans; Plasmoparaviticola; Pneumocystisjiroveci; Puccinia coronata; Puccinia gramninis;Pyricularia oryzae; Pythium ultimum; Rhizoctonia solani; Rhizomucor spp;Rhizopus spp; Scedosporium apiospermum; Scedosporium prolificans;Scedosporium species d; Scopulariopsis brevicaulis; Trichophytonmentagrophytes; Trichophyton interdigitale; Trichophyton rubrum;Trichosporon asahii; Trichosporon beigelii; and Ustilago maydis.

Preferably, the fungal disease comprises an infection by A. fumigatus,A. flavus, A. terreus, A. niger, A. lentulus, S. apiospermum, S.prolificans, or S. species d. Particularly, the fungal disease comprisesan infection by A. fumigatus, A. flavus, A. terreus or A. niger. In oneembodiment, the fungal disease comprises an infection by S. prolificans.

Examples of fungal diseases, which can be prevented or treated using acompound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) include both systemic andsuperficial infections. The fungal diseases include invasive fungaldiseases caused by Aspergillus species such as aspergillosis, but alsolocal forms of these infections. For instance, the fungal diseasesinclude invasive fungal diseases caused by Aspergillus species such asaspergillosis, but also local forms of these infections. The compound ofthe invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) is particularly usefulagainst diseases caused by Aspergillus species, for which a fungicidaldrug is required which has lower toxicity than amphotericin. Theinvention also provides for the treatment of dermatological infections.

In one embodiment, a pharmaceutical compound of the invention (forexample2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) is for use in theprevention or treatment of a disease caused by Aspergillus species. Thediseases caused by Aspergillus species include diseases caused by A.fumigatus, A. flavus, A. terreus and A. niger.

Examples of systemic infections which might be prevented or treatedusing a pharmaceutical compound of the invention (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) include: pulmonaryaspergillosis, e.g. in immunosuppressed patients such as bone marrowrecipients or AIDS patients; systemic aspergillosis; rhinocerebralmucomycosis; blastomycosis; histoplasmosis; coccidiomycosis;paracoccidiomycosis; lobomycosis; sporotrichosis; chromoblastomycosis;phaeohyphomycosis; and disseminated sporotrichosis,

Examples of superficial infections, which can be prevented or treatedusing a pharmaceutical compound (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof) include: ring worm;athlete's foot; and tinea unguium (nail infection).

Examples of diseases or conditions which are caused by fungi or wherefungi exacerbate an allergic response, and which can be prevented ortreated using a pharmaceutical compound (for example2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a pharmaceutically acceptable salt thereof), include allergicbronchopulmonary aspergillosiis (ABPA); asthma, Severe asthma withFungal Sensitisation (SAFS), fungal colonization of cystic fibrosis,rhinosinusitis and sinusitis. For instance, the disease may be caused bya fungal sensitisation, or the disease may be Allergic BronchopulmonaryAspergillosis (ABPA) or asthma.

The present invention also provides a kit comprising, in admixture or inseparate containers, a compound as defined herein, and a secondantifungal agent.

For example, the kit may comprise, in admixture or in separatecontainers, a compound, which compound is2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof, and a second antifungalagent.

Further provided by the invention is a method of preventing or treatingfungal disease in a subject which method comprises administering to saidsubject an effective amount of: (i) a pharmaceutical compound of theinvention as defined herein, (ii) a composition comprising thepharmaceutical compound, together with one or more pharmaceuticallyacceptable carriers and/or excipients, or (iii) a combinationcomprising: (a) a pharmaceutical compound of the invention; and (b) asecond antifungal agent.

The second antifungal agent may be a second antifungal agent as definedhereinabove.

The fungal disease may be a fungal disease as defined herein. Forinstance, the disease may be caused by a fungal dermatophyte.Alternatively, the disease may be Allergic BronchopulmonaryAspergillosis (ABPA) or SAFS. As a further alternative, the disease maybe asthma.

The invention also provides the use of a pharmaceutical compound,composition or combination of the invention in the manufacture of amedicament for the prevention or treatment of a fungal disease.

The second antifungal agent may be a second antifungal agent as definedhereinabove.

The fungal disease may be a fungal disease as defined herein. Forinstance, the disease may be caused by a fungal dermatophyte.Alternatively, the disease may be Allergic BronchopulmonaryAspergillosis (ABPA). As a further alternative, the disease may beasthma.

Agricultural Uses

The present invention also provides a method of controlling a fungaldisease in a plant, which method comprises applying to the locus of theplant a compound which is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof. Optionally a secondantifungal agent may also be present.

For example, the method may comprise applying to the locus of the planta compound which is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, and optionally a secondantifungal agent.

The compound (for instance2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or an agriculturally acceptable salt thereof), may, for example, beapplied to the seeds of the plants, to the medium (e.g. soil or water)in which the plants are grown, or to the foliage of the plants.

The compound (for instance2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or an agriculturally acceptable salt thereof) is preferably used in thetreatment or prevention of fungal diseases. Examples of fungal diseasesof plants which can be controlled using the compound (for instance2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof) include fungal diseasescaused by the following plant pathogens: Blumeria graminis;Colletotrichium trifolii; Fusarium graminearium; Fusarium solani;Fusarium sporotrichoides; Leptosphaeria nodorum; Magnaporthe grisea;Mycosphaerella graminicola; Neurospora crassa; Phytophthora capsici;Phytophthora infestans; Plasmopara viticola; Puccinia coronata; Pucciniagraminis; Pyricularia oryzae; Pythium ultimum; Rhizoctonia solani;Trichophyton rubrum; and Ustilago maydis.

The present invention includes an agricultural composition comprising acompound, which is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof; and an agriculturallyacceptable carrier or diluent.

The agricultural composition may, for example, comprise a compound,which is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, and an agriculturallyacceptable carrier or diluent.

Alternatively, the agricultural composition may, for example, comprise acompound, which is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, and an agriculturallyacceptable carrier or diluent

In one embodiment of the invention, the composition further comprises asecond antifungal agent. Examples include those as defined herein.

Said agricultural composition typically contains up to 85 wt % of:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof. More typically, itcontains up to 50 wt % of:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof of. When used in anagricultural composition, the skilled person will readily be able todetermine suitable levels of administration. As examples, the antifungalagent(s) can be used at a level of from 5 g to 10 kg per hectare, forexample from 10 g to 5 kg per hectare, for example from 100 g to 2 kgper hectare.

Suitable agriculturally acceptable salts include salts withagriculturally acceptable acids, both inorganic acids such ashydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitricacid and organic acids such as citric, fumaric, maleic, malic, ascorbic,succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic,benzenesulphonic or p-toluenesulphonic acid. Salts may also be formedwith agriculturally acceptable bases such as alkali metal (e.g. sodiumor potassium) and alkaline earth metal (e.g. calcium or magnesium)hydroxides and organic bases such as alkyl amines, aralkyl amines orheterocyclic amines. A preferred agriculturally acceptable salt is thehydrochloride salt.

2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, and optional secondantifungal agents, may be applied in combination with inert carriers ordiluents, as in aqueous sprays, granules and dust formulations inaccordance with established practice in the art. An aqueous spray isusually prepared by mixing a wettable powder or emulsifiable concentrateformulation of a compound of the invention with a relatively largeamount of water to form a dispersion.

Wettable powders may comprise an intimate, finely divided mixture of acompound of the invention, an inert solid carrier and a surface-activeagent. The inert solid carrier is usually chosen from among theattapulgite clays, the kaolin clays, the montmorillonite clays, thediatomaceous earths, finely divided silica and purified silicates.Effective surfactants, which have wetting, penetrating and dispersingability are usually present in a wettable powder formulation inproportions of from 0.5 to 10 percent by weight. Among the surfaceactive agents commonly used for this purpose are the sulfonated lignins,naphthalenesulfonates and condensed naphthalenesulfonates,alkylbenzenesulfonates, alkyl sulfates and non-ionic surfactants such asproducts of condensation of ethylene oxide with alkylphenols.

Emulsifiable concentrates may comprise a solution of:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, in a liquid carrier whichis a mixture of a water-immiscible solvent and a surfactant, includingan emulsifier. Useful solvents include aromatic hydrocarbon solventssuch as the xylenes, alkylnaphthalenes, petroleum distillates, terpenesolvents, ether-alcohols and organic ester solvents. Suitableemulsifiers, dispersing and wetting agents may be selected from the sameclasses of products which are employed in formulating wettable powders.

The invention also provides the use of a compound, which compound is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, optionally together with asecond antifungal agent, as an agricultural fungicide.

The use may, for example, be the use of a compound, which compound is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or an agriculturally acceptable salt thereof, optionally together with asecond antifungal agent, as an agricultural fungicide.

Alternatively, the use may, for example, be the use of a compound, whichcompound is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide,or an agriculturally acceptable salt thereof, optionally together with asecond antifungal agent, as an agricultural fungicide.

The second antifungal agent may be any antifungal agent suitable for usein agriculture. Examples include those as defined herein.

The fungicide formulations desirably contain from 0.1 percent to 95percent by weight of:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or in the case of acombination of antifungal agents the total weight of antifungal agent,and from 0.1 to 75 percent of an inert carrier or surfactant. The directapplication to plant seeds prior to planting may be accomplished in someinstances by mixing either a powdered solid of:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or a dust formulation withseed to obtain a substantially uniform coating which is very thin andrepresents only one or two percent by weight or less, based on theweight of the seed. In some instances, however, a non-phytotoxic solventsuch as methanol is conveniently employed as a carrier to facilitate theuniform distribution of:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, on the surface of theseed.

When a compound, which compound is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or in the case of acombination of antifungal agents one of the antifungal agents used, isto be applied to the soil, as for pre-emergence protection, granularformulations or dusts are sometimes more convenient than sprays. Atypical granular formulation comprises:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, dispersed on an inertcarrier such as coarsely ground clay, or clay which has been convertedto granules by treatment of a rolling bed of the powdered material witha small amount of liquid in a granulating drum. In the usual process forpreparing granular formulations, a solution of the active compound issprayed on the granules while they are being agitated in a suitablemixing apparatus, after which the granules are dried with a current ofair during continued agitation. Dust formulations customarily employessentially the same inert diluents as wettable powders and granules,but are well-mixed in powder form and do not usually containemulsifiers. Dusts may contain some surface active agents to facilitateuniform distribution of the active ingredient in the formulation and toimprove the uniformity and adhesion of the dust coating on seeds andplants. The colloidal dispersion of dust formulations in the air isusually prevented by incorporation of a minor amount of an oily or waxymaterial in the formulation to cause agglomeration of colloidal sizeparticles. In this way the dust may be applied to seeds or plantswithout generation of an air-polluting aerosol.

The following examples illustrate the invention but are not intended tolimit the scope of the invention. In this regard, it is important tounderstand that the particular assays used in the Examples section aredesigned only to provide an indication of anti-fungal activity. Thereare many assays available to determine such activity, and a negativeresult in any one particular assay is therefore not determinative.

EXAMPLES Synthesis of the Compounds of the Invention 1. Synthesis ofExample 1:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide

The synthetic scheme below provides a method of synthesis of:

2-Hydroxyimino-3-oxo-3-phenyl propionic acid ethyl ester (A)

A solution of sodium nitrite (1.07 Kg, 45.62 mol) in water (4 L) wasadded slowly to a solution of ethyl benzoyl acetate (2 Kg, 10.41 mol) inglacial acetic acid (6 L), at 0-10° C. over a period of 2 h. The productstarted precipitating during the course of addition. The reaction masswas warmed to room temperature and stirred for a further 1 h. Water (2.5L) was added and the mixture stirred for a further 1 h. Filtered undersuction, washed with water (2 L). The solid was dissolved in chloroform(8 L) and washed with water (2×500 mL), brine solution (2×500 mL), driedover anhydrous sodium sulfate and concentrated in vacuo to dryness toafford 2.0 Kg (86%) of 2-hydroxyimino-3-oxo-3-phenyl propionic acidethyl ester A as a white solid. [TLC system: Ethyl acetate: Pet ether(3:7); R_(f) value: 0.28].

5-Methyl-3-phenyl-1H-pyrrole-2,4 dicarboxylic acid diethyl ester (B)

A mixture of ethyl acetoacetate (329 g, 2.53 mol), zinc dust (443 g,6.78 mol) and anhydrous sodium acetate (463 g, 5.65 mol) in glacialacetic acid (800 mL) were heated to 60° C. A solution of A (500 g, 2.26mol) in glacial acetic acid (1.5 L) was added in three portions undervigorous stirring over a period of ˜1 h. The temperature shot up toabout 93° C. during the addition. The reaction mixture was maintained at60-75° C. for 3 h. Additional zinc dust (221 g, 3.39 mol) was added tothe reaction mass over 15 min and the mixture was stirred at 60-75° C.for 1 h, cooled to room temperature and filtered the solids. Thefiltrate was evaporated in vacuo and the residue was co-distilled withtoluene (2×500 mL). Water (5 L) and ethyl acetate (1 L) were added tothe residue and stirred till two clear layers were obtained. The organiclayer washed successively with water (2×500 mL), saturated bicarbonatesolution (2×500 mL), brine (2×500 mL) dried over anhydrous sodiumsulfate and concentrated to give 360 g of crude gummy product. This wasstirred with a mixture of dichloromethane in pet ether (200 mL: 1200 mL;1:6) at room temperature for 15 min, filtered and washed with pet ether(100 mL) to afford 250 g (36%) of 5-methyl-3-phenyl-1H-pyrrole-2,4dicarboxylic acid diethyl ester B as off-white solid. [TLC system: ethylacetate: Pet ether (3:7); R_(f) value: 0.45]. Similarly 1.5 Kg (500 g×3)of A was converted to 500 g [245 g (36%)+255 g (37%)+250 g (36%)] of Bin three batches.

1, 5-Dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester(C)

A solution of B (1 Kg, 3.322 mol) in dry tetrahydrofuran (4 L) was addedto slurry of sodium hydride (60% w/w; 254 g, 6.644 mol) in drytetrahydrofuran (4 L) at 0° C. over 1 h. The reaction mass was warmed toroom temperature and stirred for 1 h and again cooled to 0° C. Methyliodide (517 mL; 8.305 mol) was added over ½ h and the reaction mixturestirred at room temperature for 18 h. Quenched with ice-water (100 mL)and 1N hydrochloric acid (2 L) was added. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane(2×500 mL). The combined organic layers were washed successively withbrine (2×200 mL), dried over anhydrous sodium sulfate and concentratedto dryness to afford 950 g (91%) of 1, 5-dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester C as a yellow solid [TLC system: ethylacetate: Pet ether (3:7); R_(f) value: 0.56].

1, 5-Dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid (D)

A solution of sodium hydroxide (1.21 Kg, 30.25 mol) in water (3.6 L) wasadded to a solution of C (950 g, 3.025 mol) in ethanol (5 L) and heatedat reflux for 15 h. Ethanol was evaporated under reduced pressure, theresidue was diluted with water (1 L) and chilled to 0° C. Concentratedhydrochloric acid (2 L) was slowly added to adjust pH to ˜2, whilemaintaining temperature below 10° C. and stirred for 1 h. Theprecipitated solid was filtered, washed with water (1 L) and pet ether(1 L) and dried under vacuum at 60° C., to afford 550 g (70%) of1,5-Dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid D as a whitesolid. [TLC system: ethyl acetate: Pet ether (3:7); R_(f) value: 0.15].

1, 2-Dimethyl-4-phenyl-1H-pyrrole (E)

A suspension of E (550 g, 2.123 mol) in ethanolamine (1.5 L) was heatedto 175° C. (under N₂) and maintained for 1 h. The reaction mixture wascooled to room temperature, diluted with water (500 mL) and extractedwith ethyl acetate (3×200 mL). The combined organic layers were washedsuccessively with water (2×100 mL) and brine (2×100 mL), dried overanhydrous sodium sulfate and concentrated in vacuo below 40° C. to givea crude product. Flash chromatography over neutral alumina using 5%ethyl acetate in pet ether as eluent afforded 280 g (77%) of1,2-dimethyl-4-phenyl-1H-pyrrole E, as a white solid. [TLC system: ethylacetate: Pet ether (3:7); R_(f) value: 0.75].

(1, 5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-oxo-acetyl chloride (F)

Oxalyl chloride (116 mL, 1.286 mol) was added slowly to a cooledsolution of E (250 g, 1.169 mol) in dry dichloromethane (3×200 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1h. The solvent was evaporated to dryness in vacuo to afford 340 g (89%)of 1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-oxo-acetyl chloride F as abrown oily liquid. [TLC system: ethyl acetate: Pet ether (3:7); R_(f)value: 0.65]

4-Nitro phenyl piperazine (G)

A solution of 1-chloro-4-nitro benzene (650 g, 4.140 mol) in diglyme (1L) was added to a solution of piperazine (2.84 Kg, 33.12 mol) in diglyme(500 mL) at 100° C. and the resultant mass was stirred at 100° C. for 6h. The mixture was cooled to 40-45° C., water (5 L) was added; warmed toroom temperature and stirred for 1 h. The precipitated solid wasfiltered, washed with water (1 L), pet ether (500 mL) and dried to give700 g (81%) of 4-nitro phenyl piperazine G as yellow colour solid. [TLCsystem: Ethyl acetate: pet ether (3:7); R_(f) value: 0.70].

5-Fluoro-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine (H)

2-Chloro-5-fluoropyrimidine (281 g, 2.12 mol) was added to suspension of4-nitro phenyl piperazine G (400 g, 1.93 mol) and potassium carbonate(532 g, 3.85 mol) in diglyme (2.5 L), the resulting mixture was stirredat 100° C. for 6 h. On completion the mixture was cooled to 0° C. andfiltered, the solid was taken in water (5 L) and stirred for 30 mins.The suspension was filtered, the solid cake was washed with water (1 L),pet ether (1 L) and dried under vacuum to afford 500 g (85%) of5-fluoro-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine H as yellowcolour solid. [TLC system: Ethyl acetate: pet ether (3:7); R_(f) value:0.70].

4-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-phenyl amine (I)

A solution of sodium dithionite (1.27 Kg, 7.32 mol) in water (6 L) wasadded to a suspension of H (500 g, 1.83 mol) and sodium bicarbonate (614g, 7.32 mol) in methanol (6 L) at 65° C. The resultant mixture wasstirred at 65° C. for 2 h. The reaction mass was cooled to 10-15° C. andfiltered. The residue was partitioned between water (2 L) and ethylacetate (5 L), the organic layer was washed with water (2 L), brine (2L) and dried over anhydrous sodium sulfate. Concentrated in vacuo toafford 290 g (64%) of4-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-phenyl amine I as solid.[TLC system: Methanol: Chloroform (1:9); R_(f) value: 0.50].

2-(1,5-Dimethyl-3-phenyl-1H-pyrro-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide

A solution of F (332 g, 1.27 mol) in dichloromethane (3 L) was added toa stirred solution of I (290 g, 1.06 mol) and triethylamine (294 mL,2.12 mol) in dichloromethane (3 L) at 0° C. The reaction mixture waswarmed to room temperature and stirred for 30 min. The reaction mixturewas quenched with water and extracted with dichloromethane (6×500 mL).The combined organic layers were washed successively with saturatedsodium bicarbonate solution (1.5 L), water (1 L), brine (1.5 L) andfinally dried over anhydrous sodium sulfate. The organic layer wasstirred with neutral alumina (1 Kg) at room temperature for 30 min andfiltered. The filtrate was concentrated in vacuo to give the crudecompound which on washing with diethyl ether (300 mL) and followed bytrituration with ethanol (3 L) at 80° C. for 1 h and cooled to roomtemperature, filtered, washed with ethanol (500 mL) followed by hexane(200 mL) and dried to give 340 g (64%) of2-(1,5-dimethyl-3-phenyl-1H-pyrro-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl-piperazin-1yl]-phenyl}-2-oxo-acetamideas yellow color solid. [TLC System: Ethyl acetate: Pet ether (1:1);R_(f) value: 0.65].

NMR data for 2-(1,5-Dimethyl-3-phenyl-1H-pyrro-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide(¹H NMR (400 MHz, CDCl₃)) are provided in FIG. 1. The signal wasdetected in the MS spectrum at 499.1 [M+H]⁺.

2. Synthesis of Example 2:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide

2-Fluoro-5-(piperazin-1-yl) pyrimidine (K)

5-chloro-2-fluoropyrimidine (3.0 g, 22.64 mmol) was added to piperazine(9.73 g, 113.2 mmol) at room temperature. The resultant mixture washeated to 130° C. for 4 h. The reaction mixture was cooled to roomtemperature, quenched with water, extracted with dichloromethane. Thecombined organic layer was washed with water, brine, dried over sodiumsulfate and concentrated under vacuum to give the 3.5 g (85%) of2-fluoro-5-(piperazin-1-yl) pyrimidine K as solid. [TLC system:Methanol:Dichloromethane (1:9); R_(f) value: 0.21].

1-Chloro-2-(4-methoxybenzyloxy)-4-nitrobenzene (J)

4-Methoxylbenzyl chloride (2.69 g, 17.29 mmol) was added to a stirredsuspension of 2-chloro-5-nitrophenol (3.0 g, 17.29 mmol) and potassiumcarbonate (7.16 g, 51.87 mmol) in acetonitrile (30 mL) at roomtemperature. The resultant mixture was heated to 80° C. for 12 h. Thereaction mixture was cooled to room temperature, quenched with water,extracted with ethyl acetate. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate and concentrated under vacuumto give 4.0 g (80%) of 1-chloro-2-(4-methoxybenzyloxy)-4-nitrobenzene Jas solid [TLC system: Ethyl acetate: Pet ether (2:8); R_(f) value:0.71].

5-Fluoro-2-(4-(2-(4-methoxybenzyloxy)-4-nitrophenyl)piperazin-1-yl)pyrimidine L

Cesium carbonate (23.35 g, 71.67 mmol) was added to a stirred solutionof 1-chloro-2-(4-methoxybenzyloxy)-4-nitrobenzene J (3.5 g, 11.94 mmol)and 2-fluoro-5-(piperazin-1-yl) pyrimidine K (2.17 g, 11.94 mmol) intoluene (40 mL) at room temperature. The suspension was purged withargon for 20 minutes. Then2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.47 g, 1.19mmol), palladium acetate (0.806 g, 1.19 mmol) was added to thedegasified mixture, then purged with argon another 10 minutes. Theresultant mixture was heated to 120° C. for 12 h. The reaction mixturewas cooled to room temperature, quenched with water, extracted withethyl acetate. The organic layer was washed with water, brine, driedover sodium sulfate and concentrated under vacuo to give the crudecompound. Purification by column chromatography over silica gel (100-200mesh) using 20-25% ethyl acetate in pet ether as eluent afforded 4.2 g(80%) of 5-fluoro-2-(4-(2-(4-methoxybenzyloxy)-4-nitrophenyl)piperazin-1-yl) pyrimidine L as yellow color solid. [TLC system: Ethylacetate: Pet ether (1:1); R_(f) value: 0.55].

5-Amino-2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenol M

10% palladium on carbon (0.2 g) was added to a solution of5-fluoro-2-(4-(2-(4-methoxybenzyloxy)-4-nitrophenyl) piperazin-1-yl)pyrimidine L (4 g, 9.11 mmol) in methanol (20 mL) at room temperature.The resultant mixture was hydrogenated in Parr hydrogenator under 40 psipressure at room temperature for 3 h. The reaction mixture was filteredover celite and the filtrate was concentrated in vacuo to afford 1.5 g(56.9%) of 5-amino-2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenol Msolid. [TLC system: Ethyl acetate: Pet ether (1:1); R_(f) value: 0.40].

2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide(Example 2) and 5-(2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamido)-2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl2-(1,4-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetate (Example 2′)

A solution of F (1.5 g, 5.81 mmol) in dichloromethane (5 mL) was addedslowly to stirred solution of5-amino-2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl) phenol M (1.4 g,4.84 mmol) and triethylamine (1046 g, 14.52 mmol) in dichloromethane at−60° C. for 30 min. The resultant mixture was stirred for 30 minutes at−60° C. The reaction mixture was quenched with water extracted withdichloromethane. The organic layer was washed with water, brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure togive the crude compound, which was purified by column chromatographyover silica gel (100-200 mesh) using 25-75% ethyl acetate in pet etheras eluent to afford 0.557 g (22%) of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideExample 2 and 10 mg of5-(2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamido)-2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl2-(1,4-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetateExample 2′ as solid [TLC system: Ethyl acetate: Pet ether (1:1); R_(f)value: 0.32].

NMR data for2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide(¹H NMR (400 MHz, CDCl₃)) are provided in FIG. 2. The signal wasdetected in the MS spectrum at 515.3 [M+H]⁺.

NMR data for 5-(2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamido)-2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl2-(1,4-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetate (¹H NMR (400 MHz,CDCl₃)) are provided in FIG. 2b . The signal was detected in the MSspectrum at 740.43 [M+H]⁺.

3. Synthesis of Deuterated Derivative Example 3:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)phenyl)-2-oxoacetamide

Synthesis of Compound (N)

A solution of 1-chloro-4-nitro benzene (750 mg, 4.7 mmol) in diglyme (5mL) was added to a solution of piperazine-d₈ (2.71 g, 28.7 mmol) indiglyme (5 mL) at 100° C. and the resultant mass was stirred at 100° C.for 6 h. The mixture was cooled to 40-45° C., water (50 mL) was added;warmed to room temperature and stirred for 1 h. The precipitated solidwas filtered, washed with water (50 mL), pet ether (50 mL) and dried togive 800 mg (80%) of N as yellow colour solid. [TLC system: Ethylacetate: pet ether (3:7); R_(f) value: 0.70].

Synthesis of Compound (P)

2-Chloro-5-fluoropyrimidine (541 mg, 4.0 mmol) was added to suspensionof N (800 mg, 3.72 mmol) and potassium carbonate (1.0 g, 7.44 mmol) indiglyme (15 mL), the resulting mixture was stirred at 100° C. for 6 h.On completion the mixture was cooled to 0° C. and filtered, the solidwas taken in water (50 mL) and stirred for 30 mins. The suspension wasfiltered, the solid cake was washed with water (50 mL), pet ether (15mL) and dried under vacuum to afford 1.0 g (86%) of P as yellow colorsolid. [TLC system: Ethyl acetate:pet ether (3:7); R_(f) value: 0.70].

Synthesis of Compound (Q)

A solution of sodium dithionite (2.24 gm, 12.8 mmol) in water (15 mL)was added to a suspension of P (1.0 gm 3.21 mmol) and sodium bicarbonate(1.088 g, 12.8 mmol) in methanol (20 mL) at 65° C. The resultant mixturewas stirred at 65° C. for 2 h. The reaction mass was cooled to 10-15° C.and filtered. The residue was partitioned between water (30 mL) andethyl acetate (20 mL), the organic layer was washed with water (50 mL),brine (30 mL) and dried over anhydrous sodium sulfate. Concentrated invacuo to afford 800 mg (88%) of Q as white solid. [TLC system: Methanol:Chloroform (1:9); R_(f) value: 0.50].

Synthesis of Deuterated Derivative

A solution of Q (826 mg, 35.6 mmol) in dichloromethane (20 mL) was addedto a stirred solution of F (750 mg, 26.6 mmol) and triethylamine (0.750mL, 53.3 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixturewas warmed to room temperature and stirred for 30 min. The reactionmixture was quenched with water and extracted with dichloromethane (6×30mL). The combined organic layers were washed successively with saturatedsodium bicarbonate solution (50 mL), water (50 mL), brine (50 mL) andfinally dried over anhydrous sodium sulfate. The organic layer wasstirred with neutral alumina (100 g) at room temperature for 30 min andfiltered. The filtrate was concentrated in vacuo to give the crudecompound which on washing with diethyl ether (30 mL) and followed bytrituration with ethanol (20 mL) at 80° C. for 1 h and cooled to roomtemperature, filtered, washed with ethanol (10 mL) followed by hexane(20 mL) and dried to give 430 mg (89%) of the deuterated derivative asyellow color solid. [TLC System: Ethyl acetate: Pet ether (1:1); R_(f)value: 0.65].

NMR data for2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)phenyl)-2-oxoacetamide(¹H NMR (400 MHz, CDCl₃)) are provided in FIG. 3. The signal wasdetected in the MS spectrum at 507.5 [M+H]⁺.

4. Synthesis of Deuterated Derivative Example 4:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl-2,3,5,6-d₄)-2-oxoacetamide

Synthesis of Compound (R)

A solution of 1-chloro-4-nitro benzene-d₄ (2.0 g, 12.4 mmol) in diglyme(15 mL) was added to a solution of piperazine (8.5 g, 99.3 mmol) indiglyme (15 mLL) at 100° C. and the resultant mass was stirred at 100°C. for 6 h. The mixture was cooled to 40-45° C., water (50 mL) wasadded; warmed to room temperature and stirred for 1 h. The precipitatedsolid was filtered, washed with water (50 mL), pet ether (50 mL) anddried to give 2.0 g (80%) of R as yellow color solid. [TLC system: Ethylacetate: pet ether (3:7); R_(f) value: 0.70].

Synthesis of Compound (S)

2-Chloro-5-fluoropyrimidine (1.44 g, 10.9 mmol) was added to suspensionof R (2.1 g, 99.5 mmol) and potassium carbonate (2.7 g, 19.8 mmol) indiglyme (15 mL), the resulting mixture was stirred at 100° C. for 6 h.On completion the mixture was cooled to 0° C. and filtered, the solidwas taken in water (100 mL) and stirred for 30 min. The suspension wasfiltered; the solid cake was washed with water (50 mL), pet ether (50mL) and dried under vacuum to afford 2.9 g (94%) of S as yellow colorsolid. [TLC system: Ethyl acetate: pet ether (3:7); R_(f) value: 0.70].

Synthesis of Compound (T)

A solution of sodium dithionite (4.52 g, 26 mmol) in water (20 mL) wasadded to a suspension of S (2.0 gm 65 mmol) and sodium bicarbonate (2.21g, 26 mmol) in methanol (20 mL) at 65° C. The resultant mixture wasstirred at 65° C. for 2 h. The reaction mass was cooled to 10-15° C. andfiltered. The residue was partitioned between water (30 mL) and ethylacetate (20 mL), the organic layer was washed with water (50 mL), brine(30 mL) and dried over anhydrous sodium sulfate. Concentrated in vacuoto afford 1.5 g (83%) of T as white solid. [TLC system: Methanol:Chloroform (1:9); R_(f) value: 0.50].

Synthesis of Deuterated Derivative

A solution of T (715 mg, 26.9 mmol) in dichloromethane (20 mL) was addedto a stirred solution of F (835 mg, 32 mmol) and triethylamine (0.750mL, 53.3 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixturewas warmed to room temperature and stirred for 30 min. The reactionmixture was quenched with water and extracted with dichloromethane (6×30mL). The combined organic layers were washed successively with saturatedsodium bicarbonate solution (50 mL), water (50 mL), brine (50 mL) andfinally dried over anhydrous sodium sulfate. The organic layer wasstirred with neutral alumina (100 g) at room temperature for 30 min andfiltered. The filtrate was concentrated in vacuo to give the crudecompound. Crude compound was purified by Perp. HPLC to give 430 mg (89%)of the deuterated derivative as yellow color solid. [TLC System: Ethylacetate:Pet ether (1:1); R_(f) value: 0.65].

NMR data for2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl-2,3,5,6-d₄)-2-oxoacetamide(¹H NMR (400 MHz, CDCl₃)) are provided in FIG. 4. The signal wasdetected in the MS spectrum at 503.4 [M+H]⁺.

Reference Examples

Data demonstrating that2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideinhibits the growth of a wide variety of fungi are presented below. Acomparison between this pyrrole compound and structurally similarcompounds is also provided. The compounds are:

-   Example 1:    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide.-   Reference Example 1:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide.-   Example 2:    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide.-   Example 3:    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)phenyl)-2-oxoacetamide.-   Example 4:    2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl-2,3,5,6-d₄)-2-oxoacetamide.-   Reference Example 2:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide.-   Reference Example 3:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-methyl-phenyl}-2-oxo-acetamide.-   Reference Example 4:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide.-   Reference Example 5:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide.-   Reference Example 6:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide.-   Reference Example 7:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-hydroxy-phenyl}-2-oxo-acetamide.-   Reference Example 8:    N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide.-   Reference Example 9:    N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide.-   Reference Example 10:    2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide.

The synthesis of reference examples 1 to 10 is described in WO 2009130481, in the Examples section of the WO 2009 130481 specification.Information relating to the synthesis of the reference examples isincorporated herein by reference.

Activity Example: Measurement of Minimum Inhibitory Concentrations(MICs)2-(1,5-dimethyl-3-phenyl-1H-pyrro-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl-piperazin-1yl]-phenyl}-2-oxo-acetamide

Between 1 and 5 mgs of the compound were accurately weighed out into asterile Eppendorf tube. The compound was dissolved in DMSO to give asolution containing 5 mg/mL. Tubes were stored at −20° C. untilrequired.

On the day of testing thawed solutions were vortex mixed to ensurehomogeneity. 30 μL of solution was removed and added to 570 μL ofsterile water in a separate sterile Eppendorf. The thoroughly mixedsolution was used to prepare a series of doubling dilutions in water, ina deep well plate. Thirteen replicate plates were prepared using aMinitrak by aspirating 20 μL from each well into eleven clearpolystyrene 96 well plates.

Spores of Aspergillus and Scedosporium were harvested from culturesgrown on Sabarauds agar for 5 days, and resuspended in PBS/Tween 80 toapprox 1×10⁷ cfu/mL. Each organism suspension was diluted in RPMImedium, containing 2% glucose and 0.135 M MOPS buffer (pH 7.0) to0.5-2×10⁴ cfu/mL. 80 μL of an organism suspension was added to each wellof the plate containing drug dilutions.

This produced MIC plates with a drug range 50-0.05 mg/L and organisminocula of 1-2×10⁴ cfu/mL. All plates were incubated for 24-48 h at 35°C. Growth was assessed by monitoring the optical density at 485 nm foreach well. The MIC of a compound is the lowest drug concentration thatinhibits growth of an organism by >80% compared with a drug freecontrol.

The following organisms were tested. Aspergillus niger, Aspergillusfumigates, Aspergillus terreus, Aspergillus flavus, Aspergillus terreus49, Aspergillus fumigatus 210, Scedosporium apiospermum 13486,Scedosporium apiospermum 15848, Scedosporium apiospermum 451,Scedosporium apiospermum 4883, Scedosporium apiospermum 7935,Scedosporium apiospermum 8353, Scedosporium prolificans 18389,Scedosporium prolificans 206, Scedosporium prolificans 6322,Scedosporium species 15849, Scedosporium apiospermum 13486, Scedosporiumprolifican 201, Scedosporium prolifican 13486, Scedosporium prolifican7935, Scedosporium prolifican 15848, Scedosporium prolifican 8353,Scedosporium prolifican 451, Scedosporium prolifican 4883, Scedosporiumprolifican 15849, Scedosporium prolifican 1121 and Scedo apiospermum1124.

Other fungi including Absidia corymbifera; Acremonium spp; Alternariaalternata; Aspergillus nidulans; Aspergillus parasiticus; Bipolaris spp;Blastomyces dermatitidis; Blumeria graminis; Cladosporium herbarium;Coccidioides immitis; Coccidioides posadasii; Colletotrichium trifolii;Curvularia lunata; Colletotrichium trifolii; Cryptococcus neoformans;Encephalitozoon cuniculi; Epicoccum nigrum; Epidermophyton floccosum;Exophiala spp; Exserohilum rostratum; Fusarium graminearium; Fusariumsolani; Fusarium sporotrichoides; Histoplasma capsulatum; Leptosphaerianodorum; Magnaporthe grisea; Microsporum canis; Mycosphaerellagraminicola; Neurospora crassa; Paecilomyces lilanicus; Paecilomycesvarioti; Penicillium chrysogenum; Phytophthora capsici; Phytophthorainfestans; Plasmopara viticola; Pneumocystisjiroveci; Puccinia coronata;Puccinia graminis; Pyricularia oryzae; Pythium ultimum; Rhizomucor sp.;Rhizoctonia solani; Rhizomucor spp.; Rhizopus spp.; Scopulariopsisbrevicaulis; Trichophyton interdigitale; Trichophyton mentagrophytes;Trichophyton rubrum; Trichosporon asahii; Trichosporon beigelii; andUstilago maydis may also be used in the above assay. Fungi are culturedby standard methods known to those skilled in the art, and MICsdetermined as above.

Aspergillus MIC Results in Mg/L (RPMI Medium):

The following MIC results have been banded into grades. Thus, a grade ofF represents an MIC of greater than 0.06 mg/L. A grade of E representsan MIC of greater than 0.04 mg/L but less than or equal to 0.06 mg/L. Agrade of D represents an MIC of greater than 0.02 mg/L but less than orequal to 0.04 mg/L. A grade of C represents an MIC of greater than 0.01mg/L but less than or equal to 0.02 mg/L. A grade of B represents an MICof greater than 0.005 mg/L but less than or equal to 0.01 mg/L. A gradeof A represents an MIC of less than or equal to 0.005 mg/L.

Example no. A. niger A. fumigatus A. terreus A. flavus A. terreus 49 A.fumigatus 210 Example 1 C C A B A C Example 3 E E E E E E Example 4 E EE E E E Ref. Example 1 E E E F E E Ref. Example 2 E E E E E E Ref.Example 3 E E E E E E Ref. Example 4 E E E E E E Ref. Example 5 F E E EE E Ref. Example 6 F E E E E E Ref. Example 7 F F F E F F Ref. Example 8E E E E E E Ref. Example 9 E E E E E E Ref. Example 10 F D D E D D

Scedosporium MIC Results in Mg/L (RPMI Medium):

The following MIC results have been banded into grades as defined above.

Scedosporium Scedosporium Scedosporium Scedosporium ScedosporiumScedosporium apiospermum apiospermum apiospermum apiospermum apiospermumapiospermum Example no. 13486 15848 451 4883 7935 8353 Example 1 D D B CC B Ref. Example 6 F F F F F F Ref. Example 10 F F F D F E ScedosporiumScedosporium Scedosporium Scedosporium Scedosporium prolificansprolificans prolificans species apiospermum Example no. 18389 206 632215849 13486 Example 1 C D D E D Ref. Example 6 F F F F F Ref. Example 10F F E F F

Scedosporium Scedosporium Scedosporium Scedosporium Scedosporiumprolifican prolifican prolifican prolifican prolifican Example no. 20113486 7935 15848 8353 Example 1 D D C D B Scedosporium ScedosporiumScedosporium Scedosporium Scedo prolifican prolifican prolificanprolifican apiospermum Example no. 451 4883 15849 1121 1124 Example 1 BC E A A

Analogous MIC experiments to those described above showed that thecompound of Example 1 showed also good antifungal activity against S.dehoogii, S. boydii and S. aurantiacum.

In Vivo Testing Example

Summary of Survival Models of Aspergillus fumigatus Infection

Murine survival models are frequently used to assess the efficacy ofantifungal drugs against Aspergillus. The models used in the developmentof Example 1 were carried out at Euprotec Ltd (Manchester) a contractresearch organisation (CRO) with extensive experience in the evaluationof antifungal drugs. The typical model involves the use of groups of6-10 male CD-1 mice per treatment group. Mice are immunosuppressed with200 mg/kg cyclophosphamide injected intraperitoneal 3 days prior toinfection. A. fumigatus strain A1163 is cultured on Sabourauds agar for4-6 days at 35° C. Spores are harvested in phosphate buffered saline (PBS)/Tween, the suspension diluted and the number of spores enumerated.Mice are then infected with an intravenous injection of A. fumigatusspores given through the lateral tail vein. The typical inoculum is6-8×10⁴ cfu/mouse and is sufficient to kill all untreated animals by Day4-6. The animals die of IA and Aspergillus organisms can be detected inmany body tissues. Treatment is typically commenced soon after infectionbut delays of up to 24 h following infection produce a more challengingmodel. Treatment is continued for 7-9 days. Treatment may be up to 3times daily using an oral dosing. Following cessation of treatment,animals are observed for 1-2 days, and then sacrificed. Relevantcontrols treated with oral drug-free vehicle are always included;ideally there should be no survivors in this group. A positive controlconsisting of an antifungal drug such as Reference Example 10 was used.This compound consistently produces 100% survival at doses of 10 mg/kgb.i.d. dosed by the oral route. Most models are run as temporaryneutropenic models where only a single dose of cyclophosphamide isadministered.

The fungal burden in the kidney can be determined on animals survivingto the end of the study and this can help provide efficacydiscrimination between groups where all animals survive. Tissue burdensare carried out by removing the kidneys from animals when they areculled at the end of the study. These are homogenised in saline andplated onto Sabourauds agar and incubated at 35° C. for 72 h.Aspergillus colonies are counted and the amount of aspergillus per gramof kidney calculated. The results are expressed as colony forming unitsper gramme (cfu/g). One of the problems with tissue burden studies isthe lack of comparable controls, as vehicle treated animals all diebefore the end of the study. However, data from studies where tissueburden has been carried out on untreated animals at day 4 or 5 has shownthat tissue burdens are typically in excess of 20,000 cfu/g and mayexceed 100,000 cfu/g in some studies.

Galactomannan Measurements

Galactomannan is a carbohydrate material present in the cell wall ofaspergillus. As the organism grows galactomannan is secreted into theextracellular medium. It can be found in the plasma of infected humansand animals, and its presence is a strong indicator of active disease.Detection of galactomannan in human plasma is now considered animportant diagnostic test for human aspergillosis. More recently it hasbeen shown that successful treatment of aspergillosis with drugs such asvoriconazole can reduce galactomannan concentrations in serum in bothhumans and animals, allowing sequential galactomannan indices to be usedas a measure of therapeutic efficacy. Galactomannan measurements canpotentially be a useful biomarker for assessing the response toantifungal therapy in clinical trials. Rising levels indicatetherapeutic failure whilst falling levels indicate therapeutic success.However, the echinocandin drugs such as caspofungin although they areefficacious in animal models of aspergillosis do not reducegalactomannan levels. The purpose of this work was to determine ifExample 1 reduced galactomannan levels in mouse aspergillosis infectionmodels and whether this could be used as a marker to predict efficacy infuture work.

In some of the survival studies described below serum samples werecollected from surviving mice at the end of the study or on mice thatsuccumbed to infection during the study to examine the effect of Example1 on galactomannan levels and to see if there was a relationship betweengalactomannan levels and survival.

The galactomannan assays were carried out on serum samples that had beenstored frozen at −80° C. Samples were thawed and assayed using aPlatelia Aspergillus Ag enzyme-linked immunosorbent assay (ELISA) kit(Biorad). The assay was modified slightly to take into account the smallsample volumes available from mice. If assay results were high a repeattest was carried out on a sample diluted in normal mouse serum. Theamount of galactomannan in a sample is presented as a galactomannanindex. The mean galactomannan index for each group was calculated and ispresented graphically against each treatment regimen.

Survival Study

The survival study carried assessed the dose response of Example 1.Example 1 was dosed orally to A. fumigatus infected mice at 2 doselevels 10 mg/kg b.i.d. and 3 mg/kg b.i.d. Therapy was initiated at 24 hpost infection and therapy continued for 8 days. At the end of the studykidney burdens were measured on surviving animals. In addition serumsamples were taken at the end of the study from all surviving animalsand from each animal that died during the course of the study. Thesewere stored frozen at −80° C. for galactomannan measurements. Thesurvival curves are shown in FIG. 5.

This study shows that Example 1 dosed orally at 10 mg/kg b.i.d. givesexcellent efficacy in murine models of invasive aspergillosis. Oraldoses of 3 mg/kg b.i.d. Example 1 show some efficacy in this model butare unable to prevent death in all animals. End of study tissue burdenswere 1114 cfu/gm and 3021 cfu/gm for 10 mg/kg b.i.d. and 3 mg/kg b.i.d.respectively.

The galactomannan indices obtained in survival study 3 are shown in FIG.6. The 10 mg/kg b.i.d. dose of Example 1 which produced 100% survival atend of study produced very low galactomannan indices. The animalstreated with the 3 mg/kg b.i.d. dose of Example 1 produced only 10%survival at the end of study and the galactomannan indices werecorrespondingly high, of a similar magnitude to those from untreatedanimals. This clearly demonstrates that low galactomannan indicescorrelate well with survival, and that when dosed orally at a suitabledose Example 1 is able to reduce galactomannan indices in A. fumigatusinfected mice.

Lomentospora prolificans FMR 3569 Against Example 1 in DisseminatedInfection Model

Culture

L. prolificans (also known as Scedosporium prolificans or S.prolificans) was grown on Potato Dextrose Agar (PDA) for 5 days at 35°C. On the day of infection, cultures were flooded with sterile salineand filtered through sterile gauze to remove clumps of conidia andhyphae. The resulting suspensions were adjusted by haemocytometer countand by serial plating to confirm viability.

Animals

Male OF-1 mice with a mean weight of 30 g were used in the experiment.Mice were housed in standard boxes with food and water ad libitum. Allanimal procedures were supervised and approved by the Universitat Rovirai Virgili Animal Welfare and Ethics Committee.

Immunosuppression

Mice were rendered neutropenic two days prior to infection by anintraperitoneal (i.p.) injection of 200 mg/kg of cyclophosphamide, andonce every 5 days thereafter (Clemons et al, 2005).

Infection

Mice were challenged with 5×10⁴ CFU/animal of L. prolificans FMR 3569,in a volume of 0.2 ml of sterile saline into the lateral tail vein.

Treatment

Treatments consisted of (a) voriconazole (VRC) (Vfend; Pfizer S. A.,Madrid, Spain) at 25 mg/kg p.o, by gavage QD; (b) Example 1 at 20 mg/k,p.o, by gavage BID; and (c) no treatment. From 3 days before infection,mice that received VRC were given grapefruit juice instead of water(Sugar & Liu, 2001). All treatments began 1 day after challenge, and thetherapy lasted for 9 days. Controls received no treatment.

For survival studies groups of 10 mice were randomly established foreach therapy. Mortality was recorded daily until the end of theexperiment. For tissue burden studies groups of 5 animals wereperformed. Mice were checked twice a day, on day 13 post infectiontissue burden groups were euthanized by CO₂ anoxia. Lung, kidney andbrain were removed, homogeneized in sterile saline and plated onto PDAfor CFU/g of tissue calculation.

Statistical Analysis

The mean survival times (MST) were estimated by the Kaplan-Meier methodand compared among groups by using the log rank test. In tissue burdenstudies, colony counts were log₁₀-transformed and compared by thetwo-tailed Mann-Whitney U-test, using Graph Pad Prism 5 for Windows. Pvalues ≦0.05 were considered statistically significant.

Survival Results

Survival results are presented in FIG. 7. It is clear from the datapresented that the use of voriconazole provides no significant increasein the survival rates when compared with the control. Example 1, incontrast, provides improved survival rates.

Survival Statistics

Treatment Control VRC Example 1 Control — — — VRC 0.89 — — Example 10.159 0.01 —

Tissue Burden Statistics

Kidney Organ Lung (control) (control) Brain (control) Lung (VRC 25mg/kg) 0.4 — — Kidney (VRC — >0.99  — 25 mg/kg) Brain (VRC 25 mg/kg) — —0.62 Lung (Example 1 0.0396 — — 20 mg/k BID) Kidney (Example 1 — 0.07 —20 mg/k BID) Brain (Example 1 — — 0.13 20 mg/k BID) Lung Kidney Brain(VRC 25 mg/k) (VRC 25 mg/k) (VRC 25 mg/k) Lung (Example 1 0.22 — — 20mg/k BID) Kidney (Example 1 — 0.01 — 20 mg/k BID) Brain (Example 1 — — 0.0412 20 mg/k BID)

1. A compound, which compound is: (a)

2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a deuterated derivative thereof, or (b)

2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor a deuterated derivative thereof, or (c) a prodrug of compound (a) ora prodrug of compound (b), or a pharmaceutically acceptable salt oragriculturally acceptable salt of (a), (b) or (c).
 2. A compoundaccording to claim 1, which compound is: (a)2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor a deuterated derivative thereof, or (b)2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor a deuterated derivative thereof, or (c) a prodrug of compound (a) ora prodrug of compound (b), or a pharmaceutically acceptable salt of (a),(b) or (c)
 3. A compound according to claim 1, which compound is: 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof.
 4. A compound accordingto claim 1, which compound is: 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide,or a pharmaceutically acceptable salt thereof.
 5. A compound accordingto claim 1, which compound is a prodrug of:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide;or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamide,which prodrug is:

wherein: R is a group of formula —O—CO—OR¹, —O—CO—R¹, —O—CO—NR¹R²,—O—CO—(CH₂)_(z)—NR¹R², —OR¹, —O—(CR¹R²)_(z)—O—CO—R³—, —O—P(O)(OR⁴)(OR⁵)or —O—(CH₂)_(z)—O—P(O)(OR⁴)(OR⁵), wherein: R¹, R² and R³ areindependently hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6cycloalkyl, an unsubstituted 5- to 7-membered heterocyclyl group, or a5- to 7-membered heterocyclyl group substituted with up to threesubstituents selected from C1-C4 alkyl and C1-C4 alkoxy; R⁴ and R⁵ areindependently hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or agroup I element; and z is 1, 2, 3 or 4; or a pharmaceutically acceptablesalt of the prodrug.
 6. A compound according to claim 5 wherein R is agroup of formula —O—CO—OR¹, —O—CO—R¹, —O—CO—NR¹R²,—O—CO—(CH₂)_(z)—NR¹R², —OR¹, —O—(CR¹R²)_(z)—O—CO—R³ or—O—P(O)(OR⁴)(OR⁵), wherein: R¹, R² and R³ are independently hydrogen,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, or anunsubstituted 5- to 6-membered heterocyclyl group; R⁴ and R⁵ areindependently hydrogen, C1-C4 alkyl, or a group I element; and z is 1 or2, or a pharmaceutically acceptable salt thereof.
 7. A compoundaccording to claim 5 or claim 6 wherein R is a group of formula —O—COR¹,—O—CO—NR¹R², —O—CO—(CH₂)_(z)—NR¹R², —OR¹, —O—(CR¹R²)_(z)—O—CO—R³ or—O—P(O)(OR⁴)(OR⁵), wherein R¹, R² and R³ are independently hydrogen,C1-C4 alkyl, C3-C6 cycloalkyl, or an unsubstituted pyrrolidinyl,piperazinyl, tetrahydropyranyl or piperidinyl group; R⁴ and R⁵ areindependently hydrogen, methyl, ethyl, or Na; and z is 1, or apharmaceutically acceptable salt thereof.
 8. A compound according toclaim 1, which compound is: (i) a deuterated derivative of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamidewherein: (a) all of the hydrogen atoms on the piperazinyl ring arereplaced with deuterium

(b) all of the hydrogen atoms on the phenyl ring adjacent to thepiperazinyl ring are replaced with deuterium

 or (c) all of the hydrogen atoms on the pyrimidinyl ring are replacedwith deuterium

 or (ii) a deuterated derivative of2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamidewherein: (a) all of the hydrogen atoms on the piperazinyl ring arereplaced with deuterium

 or (b) all of the hydrogen atoms on the phenyl ring adjacent to thepiperazinyl ring are replaced with deuterium

 or (c) all of the hydrogen atoms on the pyrimidinyl ring are replacedwith deuterium

 or or a pharmaceutically acceptable salt of deuterated derivative (i)or (ii).
 9. A pharmaceutical composition comprising a compound asdefined in any one of claims 2 to 8 together with one or morepharmaceutically acceptable carriers and/or excipients.
 10. Apharmaceutical combination comprising: (i) a compound as defined in anyone of claims 2 to 8; and (ii) a second antifungal agent.
 11. Apharmaceutical combination according to claim 10, wherein the compound(i) and the second antifungal agent (ii) are formulated for separate,simultaneous or successive administration.
 12. A pharmaceuticalcombination according to claim 10 or claim 11, wherein the secondantifungal agent is selected from the group consisting of azoles,polyenes, purine nucleotide inhibitors, pyrimidine nucleotideinhibitors, mannan inhibitors, protein elongation factor inhibitors,echinocandins, allylamines, anti-HSP90 antibodies,bactericidal/permeability inducing protein products or polyoxins, or oneof the compounds 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborale,5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborale, icofungipen, VT116 orSCY078.
 13. A pharmaceutical combination according to claim 12, whereinthe second antifungal agent is (a.i) an azole selected fromclotrimazole, econazole, bifonazole, butoconazole, fenticonazole,fluconazole, isoconazole, itraconazole, ketoconazole, miconazole,oxiconazole, sertaconazole, sulconazole, tioconazole, isavuconazole,ravuconazole, posaconazole, terconazole and voriconazole; (a.ii) anechinocandin selected from anidulafungin, caspofungin and micafungin;(a.iii) an allylamine selected from terbinafine, butenafine, amorolfineand naftifine; (a.iv) a polyene selected from amphotericin B andnystatin; (a.v) a purine or pyrimidine nucleotide inhibitor which isflucytosine; (a.vi) a mannan inhibitor which is pradamicin; (a.vii) aprotein elongation factor inhibitor selected from sordarin and analoguesthereof; or (a.viii) a polyoxin which is nikkomycin Z.
 14. Apharmaceutical composition according to claim 9 comprising (i) acompound as defined in any one of claims 2 to 8, (ii) a secondantifungal agent as defined in any one of claims 10 to 13, and (iii) oneor more pharmaceutically acceptable carriers and/or excipients.
 15. Acompound according to any one of claims 2 to 8, a composition accordingto claim 9 or 14 or a combination according to any one of claims 10 to13 for use in a method of treatment of the human or animal body bytherapy.
 16. A compound according to any one of claims 2 to 8, acomposition according to claim 9 or 14 or a combination according to anyone of claims 10 to 13 for use in the prevention or treatment of fungaldisease.
 17. A compound, composition or a combination for use accordingto claim 16, wherein the compound is for use in the prevention ortreatment of a fungal disease, by intravenous administration.
 18. Acompound, composition or combination for use according to claim 15 orclaim 16 wherein the disease is caused by an Aspergillus species.
 19. Acompound, composition or combination for use according to claim 15 orclaim 16 wherein the disease is caused by a fungal dermatophyte, orwherein the disease is Allergic Bronchopulmonary Aspergillosis (ABPA) orasthma.
 20. A kit comprising, in admixture or in separate containers, acompound as defined in any one of claims 1 to 8 and a second antifungalagent as defined in any one of claims 10 to
 13. 21. A method ofcontrolling a fungal disease in a plant, which method comprises applyingto the locus of the plant a compound which is:2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, and optionally a secondantifungal agent.
 22. Use of a compound, which compound is: 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, or2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-3-hydroxyphenyl)-2-oxoacetamideor an agriculturally acceptable salt thereof, optionally together with asecond antifungal agent, as an agricultural fungicide.
 23. A method ofpreventing or treating fungal disease in a subject which methodcomprises administering to said subject an effective amount of acompound as defined in any one of claims 2 to 8, a composition accordingto claim 9 or 14 or a combination according to any one of claims 10 to13.
 24. A method according to claim 23, wherein disease is caused by afungal dermatophyte.
 25. A method according to claim 23, wherein thedisease is Allergic Bronchopulmonary Aspergillosis (ABPA).
 26. A methodaccording to claim 23, wherein the disease is asthma.
 27. The use of acompound as defined in any one of claims 2 to 8, a composition accordingto claim 9 or 14 or a combination according to any one of claims 10 to13 in the manufacture of a medicament for the prevention or treatment ofa fungal disease.
 28. The use according to claim 27, wherein the diseaseis caused by a fungal dermatophyte.
 29. The use according to claim 27,wherein the disease is Allergic Bronchopulmonary Aspergillosis (ABPA).30. The use according to claim 27, wherein the disease is asthma.